17alpha-ethynyl-10beta-propyl-delta4, 9(11)-estradiene-17beta-ol-3-one and its preparation



United States Patent 16 Claims. (Cl. 260340.9)

H5 CH TOH I 05011 5 The invention also relates to a novel process forthe preparation of the said novel product and to novel intermediates,formed therein.

17 a ethynyl 105 propy1-A -estradiene-175-01-3- one possesses usefulphysiological properties, particularly progestomimetic activity, and canbe administered orally.

It is an object of the invention to provide the novel product, 17aethynyl-10,8-propyl-A -estradiene-17B- ol3-one.

It is another object of the invention to provide a novel process for thepreparation of l7a-ethynyl-1OB-propyl- A -estradiene-17B-ol-3-one.

It is a further object of the invention to provide novel intermediatesfor 170: ethynyl-10B-propyl-A -estradiene-17fi-ol-3-one.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

The novel product of the invention, l7ct-ethynyl-10B- propyl-A-estradiene-l7fi-ol 3-one has the structural formula TOE I CECE Theprocess of the invention for the preparation of 17aethynyl 10fl-propyl-A-estradiene-l7l3-ol-3 one comprises catalytically hydrogenating3.-lo,wer alkylenedioxy- 175 acyloxy 10B allyl 4,5 seco A -estrene-5-onewherein the acyl radical is derived from an organic carboxylic acidhaving 1 to 18 carbon atoms to form 3-l0wer alkylenedioxy 17/3 acyloxy10fl-propyl-4,5-seco-A estrene-5-one, hydrolyzing the latter underacidic conditions to form 175 acyloxy 10fi-propyl-4,5-seco-Aestrene-3,5-dione,, simultaneously cyclizing and saponifying the latterunder alkaline conditions to form 10,6- propyl-A-estradiene-17fi-o1-3-one, oxidizing the latter to form lOfl-propyl-A-estradiene-3,17-dione, reacting the latter with a lower alkylorthoformate to form 3-lower alkoxy 10fl-propyl-A -estratriene-17-one,reacting the latter with an ethynylation agent to form 3-lower alkoxylOfi-propyl-17a-ethynyl-A -estratriene-17,8- ol, hydrolyzing the latterunder acid conditions to form a ethynyl 1Ofi-propyl-A-estradiene-17fl-ol-3-one and recovering the latter.

A preferred mode of the process of the invention for the preparation ofHot-ethynyl-10fi-propyl-A -estradiene-17fl-ol-3-one comprisescatalytically hydrogenating 3 ethylenedioxy 17B benzoyloxy 10/3allyl-4,5-seco- A -estrene-5-0ne in the presence of a palladium catalystsuch as palladized carbon black to form3-ethylenedioxybenzoyloxy-l0/3-propyl-4,5-seco-A -estrene-5one,hydrolyzing the latter in the presence of an organic acid such as aceticacid to form 17fi-benzoyloxy-IOB-propyl- 4,5-seco-A -estrene-3,S-dione,simultaneously cyclizing and saponifying the latter in the presence ofan alkali metal hydroxide in a lower alkanol such as potassium hydroxidein methanol to form 1OB propyl-A -estra diene-l7fl-ol-3-one, oxidizingthe latter with chromium trioxide to form 10fi-propyl-ALestradiene-3,l7-dione, reacting the latter with ethyl orthoformate inthe presence of p-toluene sulfonic acid to form 3-ethoxy-10fl-propyl- A-estratriene-l7-one, reacting the latter with an alkali metal acetylidesuch as potassium acetylide to form 3 ethoxy 17a ethynyl-10B-propyl-A-estratriene 175-01, hydrolyzing the latter with a mineral acid such ashydrochloric acid to form Not-ethynyl-10fl-propyl-Aestradiene-17B-ol-3-one and recovering the latter. The reaction schemeis illustrated in Table I.

TABLE I 0 Hg 0 H 0 H AH H2 2 WJ fijOR @130 R O 0 k 0 0/ O 0/ (II) (III)(IV) 3 4 TABLE I-Continued H1 H2 on, (311,

v on, (v) on, 1) (EH; +5, (in, on, CH; CH; CH;

0 on orr i I 05011 050E R R30 O (VII) (VIII) I (I) wherein R is an acylradical of an organic carboxylic acid having 1 to 18 carbon atoms, R isa lower alkylene radical and R is a lower alkyl radical having 1 to 7carbon atoms.

The acyl radical of the organic carboxylic acid having 1 to 18 carbonatoms may be derived from an aliphatic, aromatic, cycloaliphatic orheterocyclic carboxylic acid. Examples of suitable acids are alkanoicacids, such as formic acid, acetic acid, propionic acid, butyric acid,iso butyric acid, valeric acid, isovaleric acid, trimethyl acetic acid,caproic acid, ,B-trimethyl propionic acid, heptanoic acid, caprylicacid, pelargonic acid, capric acid, undecylic acid, lauric acid,myristic acid, palmitic acid and stearic acid; alkenoic acids such asundecylenic acid and oleic acid; cycloalkyl carboxylic acids such ascyclopentyl car boxylic acid, cyclopropyl carboxylic acid, cyclobutylcarboxylic acid and cyclohexyl carboxylic acid; cycloalkyl alkanoicacids such as cyclopentyl acetic acid, cyclohexyl acetic acid,cyclopentyl propionic acid and cyclohexyl propionic acid; arylalkanoicacids such as phenyl acetic acid and phenyl propionic acid; arylcarboxylic acids such as benzoic acid and 2,4-dinitrobenzoic acid;phenoxy alkanoic acids such as phenoxy acetic acid, p-chlorophenoxyacetic acid, 2,4-dichlorophenoxy acetic acid, 4-ter-butylphenoxy aceticacid, 3-phenoxy propionic acid and 4- phenoxy butyric acid; heterocycliccarboxylic acids such as furane-Z-carboxylic acid,5-ter-butylfurane-2-carboxylic acid, 5-bromofurane-2-carboxylic acid andnicotinic acids; fi-ketoalkanoic acids, such as acetylacetic acid,propionylacetic acid and butyrylacetic acid; amino acids such asdiethylaminoacetic acid and aspartic acid.

The 3-lower alkylenedioxy-17fl-acy1oxy-10fl-allyl-4,5- seco-A-estrene-S-ones which are the starting materials for the process of theinvention are prepared by a1- lylation of the corresponding 3-loweralklenedioxy-17,8- acyloxy-4,5-seco-A -estrene 5 ones, the latter beingprepared according to US. patent application serial number 83,381, filedJanuary 18, 1961, now Patent No. 3,117,979.

In the following examples there are described several preferredembodiments to illustrate the invention. However, it should beunderstood that the invention is not intended to be limited to thespecific embodiments.

EXAMPLE I Preparation of 3-Ethylenedi0xy-1 7,8-Benzoyl0xy-1018- Allyl-4,5-Seco-A -Estrene-5-One 4.5 g. of 3-ethylenedioxy-17fibenzoyloxy- 4,5 seco- A -estrene-5-one (obtained according to U.S.patent application Serial Number 83,381) dissolved in 45 cc. ofanhydrous toluene were introduced into 13 cc. of a was allowed to standat room temperature for a period of 3 hours. The reaction mixture waspoured into water and extracted with ether. The ethereal extracts werewashed with water, dried and evaporated to dryness under vacuum. Theresidue was subject to chromatography through magnesium silicate andeluted with methylene chloride containing 2% of ether.3-ethylenedioxy-17/3- benzoyloxy-1O 8-allyl-4,5-seco-A -estrene-5-onewas obtained having a melting point of 128 C. and a specific rotation[ix] =[-6Qi1 (c.=0.5% in methanol).

The product occurred in the form of white rodlets, and was soluble inalcohol, ether, acetone, benzene and chloroform, and insoluble in Water.

Analysis.C H O molecular weight=478.60. Calculated: C, 75,28%; H, 8.00%.Found: C, 75.1%; H, 7.9.

EXAMPLE II Preparation of 17a-Ethynyl-10fi-Pr0pyl-AEstradiene-1'7B-Ol-3-0ne STEP A.-3-ETHYLYENEDIOXY-17B-BENZOYLOXY-1OB-PROPYL-l,5-SECO-A -ESTRENEfi-ONE 100 mg. of3-ethylenedioxy-l7;3-benzoyloxy-IOB-allyl- 4,5-seco-A -estrene-S-onewere introduced into 10 cc. of ethyl acetate containing 1% oftriethylamine and 10 mg. of palladized carbon black containing 15% ofpalladium were added. The reaction mixture was hydrogenated for a periodof 15 minutes. Then the catalyst was filtered and the filtrate was thenevaporated to dryness under vacuum. The residue was crystallized frommethanol and furnished 3-ethylenedioxy-17/3-benzoyloxy-10B-propyl-4,5-seco-A -estrene-S-one having a melting point of C. and aspecific rotation [a] =+60:l (c.=0.6% in methanol).

The product occurred in the form of colorless prismatic crystals and wassoluble in most of the usual organic solvents such as benzene,chloroform, alcohol, ether, acetone, and insoluble in water.

Analysis.C H O molecular weight=480.62. Calculated: C, 74.96%; H, 8.38%.Found: C, 74.8%; H, 8.3%.

A"(11)-ESTRENE-3,5 DIONE 1.4 g. of3-ethylenedioxy-17,8-benzoyloxy-IOfl-propyl- 4,5-seco-A -estrene-S-onewere introduced into 91 cc. of a 75% acetic acid solution under anatmosphere of nitrogen. The mixture was heated to 60 C. for a period ofone hour and after cooling, the mixture was poured into water saturatedwith sodium bicarbonate and extracted with ether. The ethereal extractswere washed with water, dried, and evaporated to dryness under vacuum.The residue was crystallized from isopropyl ether and furnished17fi-benzoyloxy-10,B-propyl-4,5 seco-A -estrene-3,5-dione, having amelting point of 7576 C. and a specific rotation [u] =+'65i1 (c.=0.6% inmethanol).

The product occurred in the form of white prismatic crystals, and wassoluble in alcohol, ether, acetone, benzene and chloroform, andinsoluble in water.

Ar qlysis.C H O molecular weight=436.57. Calculated: C, 77.02%; H,8.31%. Found: C, 77.1%; H, 8.1.

STEP C.1Ofi-PROPYL-N -ESTRADIENE-17B-OL-3-ONE 1.2 g. of17fl-benzoyloxy-10fl-propyl-4,5-seco-A -estrene-3,5dione were introducedinto 120 cc. of a 0.5 N solution of potassium hydroxide in methanolunder an atmosphere of nitrogen. The reaction mixture was heated toreflux for a period of one hour and then evaporated to dryness undervacuum. The residue was taken up in water and extracted with methylenechloride. The methylene chloride extracts were washed with water, drledand evaporated to dryness under vacuum. The residue was purified bysubjecting it to chromatography through magnesium silicate and elutionwith methylene chloride containing 4% of ether. fl-propyl-Aestradiene-l7fl-ol-3-one having a melting point of 125 C. and a specificrotation [a] =|87.5 C. (c.-=0.6% in methanol) was obtained.

The product occurred in the form of white crystals soluble in alcohol,ether, benzene and chloroform and insoluble in water.

Analysis.-C H O molecular weight=314.45. Ca1- culated: C, 80.20%; H,9.61%; O, 10.17%. Found: C, 80.0%; H, 9.4%; O, 10.4%.

U.V. spectra in ethanol: A 240-241 III/L, e=16,450.

STEP D.1OB-PROPYL-A ESTRADIENE-3JT-DIONE 1.625 g. of l0B-propyl-A-estradiene-l7fi-ol-3-one Were dissolved in 200 cc. of acetic acid. Veryslowly, 1 g. of chromium trioxide in solution in 10 cc. of 90% aceticacid was added and the reaction mixture was agitated at room temperaturefor a period of one hour and twenty minutes. 40 cc. of methanol wasadded thereto and the agitation was continued for another minutes. Thenthe reaction mixture was poured into water saturated with sodiumbicarbonate and the solution was extracted with ether. The etherealextracts were washed with water, dried, and evaporated to dryness undervacuum. The residue consisted of 1OB-propyl-A -estradiene-3,17-dionewhich was purified by chromatography through magnesium silicate andelution with methylene chloride containing 2% of acetone. A whitecrystalline product having a melting point of 120-122 C. and a specificrotation [a] =+194- C. (c.=0.7% in methanol) was obtained.

The product was soluble in ether, acetone, benzene and chloroform,slightly soluble in alcohol and insoluble in water.

Analysis.C H O molecular Weight =312.43. Ca1- culated: C, 80.72%; H,9.03%. Found: C, 80.4%; H, 9.0%.

U.V. spectra in ethanol: k 241 III/L, e=16,l00.

STEP E.3-ETHOXY-10B-PROPYL-A ESTRATRIENEHLONE 400 mg. of l0,8-propyl-A-estradiene-3,17-dione were dissolved in 2 cc. of hot ethanol containing0.4 cc. of ethyl orthoformiate. Several drops of a solution of p-toluenesulfonic acid in ethanol were added and the reaction mixture wasmaintained at 70 C. under agitation in an atmosphere of nitrogen for aperiod of fifteen minutes. After the addition of several drops oftriethylamine the reaction mixture was poured into water and the aqueousmixture was extracted with methylene chloride. The methylene chlorideextracts were washed with water, dried and evaporated to dryness undervacuum. 480 mg. of raw 3-ethoxy-10B-propyl-A -estratriene- 17-one wereobtained.

The product, which is not described in the literature, was utilized assuch for the next step.

Infrared spectra:

17-one at 1744 cm. Enolic ether at 1655 and 1629-cm."

3 g. of potassium shavings were introduced in small amounts into amixture of 30 cc. of ter-amyl alcohol and 12 cc. of benzene. Thereaction mixture was agitated for a period of one hour in an atmosphereof nitrogen at 5560 C. Then a stream of acetylene was passedtherethrough and the agitation was continued for another two hours at 55-60 C.

The reaction mixture was cooled to room temperature and 460 mg. of3-ethoxy-10,8-propyl-A -estratriene- 17-one were introduced. Thismaterial was obtained according to the preceding step and was in asolution of 12 cc. of benzene and 12 cc. of ether. The reaction mixturewas agitated for a period of two hours at 25 C. under a stream ofacetylene. 10 cc. of water were added to the reaction mixture, and themixture was decanted. The organic phase was washed with water and withaqueous sodium bicarbonate, dried and evaporated to dryness undervacuum. 530 mg. of raw 3-ethoxy-10flpropyl-17a-ethynyl-A -estratriene-178-01 were obtained.

The product, which is not described in the literature, was utilized assuch for the following step.

530 mg. of raw 3-ethoxy-l7a-ethynyl-10 8-propyl-A -estratriene-17fl-olobtained according to the preceding step were dissolved in 7 cc. of hotethanol under agitation in an atmosphere of nitrogen. 0.7 cc. of normalaqueous hydrochloric acid were added and the reaction mixture was heatedto 5060 C. for a period of five minutes. Then the reaction mixture waspoured into water and the mixture was extracted with methylene chloride.The methylene chloride extracts were washed with water, dried, andevaporated to dryness under vacuum. 440 mg. of product were obtainedwhich was subjected to chromatography through magnesium silicate. Aftercrystallization from isopropyl ether, 190 mg. of 170:.-ethynyl-1()fl-propyl-A -estradiene-17B-ol-3-one having a melting pointof C., then 142-144 C. and a specific rotation [a] =0 (c.=0.5% inmethanol) were recovered. The product contained 11% of isopropyl etherof solvation.

The product occurred in the form of white prisms, insoluble in water anddilute aqueous acids and alkalis, slightly soluble in isopropyl ether,and solubel in alcohol, ether, acetone, benzene and chloroform.

Analysis.C H O molecular weight=338.47. Calculated: C, 81.61%; H, 8.93%.Found: C, 81.7%; H, 8.8%.

The product is not described in the literature.

Various modifications of the process of the invention may be madewithout departing from the spirit or scope thereof, and it is to beunderstood that the invention is intended to be limited only as definedin the appended claims.

wherein R is an acyl radical of an organic carboxylic acid having 1 to18 carbon atoms and R is lower alkylene.

2. 3-ethylenedioxy 17/3 benzoyloxy-10B-propyl-4,5- seco-A-estrene-S-one.

3. A compound having the formula Hg CH3 wherein R is an acyl radical ofan organic carboxylic acid having 1 to 18 carbon atoms.

4. 17/3 benzoyloxy 105 propyl-4,5-seco-A -estrene-3,5-dione.

5. A compound having the formula CH OH;

I If

wherein R is lower alkyl having 1 to 7 carbon atoms.

6. 3-eth0xy-lOfi-propyl-A -estratriene-17-one. 7. A compound having theformula H2 CH TOH l I 05011 wherein R is lower alkyl having 1 to 7carbon atoms.

8. 3-ethoxy 170a ethynyl-l0,8-propyl-A -estratriene-17,B-ol.

9. A process for the preparation of 17a-ethyny1-10fipropyl-A-estradiene-17,6-01-3-one which comprises catalytically hydrogenating3-lower alkylenedioxy-Uflacyloxy-1OB-allyl-4,5-seco-A -estrene 5 onewherein the acyl radical is derived from an organic carboxylic acidhaving 1 to 18 carbon atoms in the presence of a palladium catalyst toform 3-lower alkylenedioxy-17fiacyloxy-10fl-propyl-4,5-seco-A -estrene 5one, hydrolyzing the latter under acidic conditions to form acyloxy 10Bpropyl-4,5-seco-A -estrene-3,5-dione, simultaneously cyclizing andsaponifying the latter in the presence of an alkali-metal hydroxide in alower alkanol to form 10p-propyl-A -estradiene-l7fi-ol-3-one, oxidizingthe latter with chromium trioxide to form IOfl-propyl- M-estradiene-Zi,17-dione, reacting the latter with a lower alkylorthoformate to form 3-lower alkoxy-lOfl-propyl-A -estratriene-17-one,reacting the latter with an alkali metal acetylide to form 3-loweralkoxy-lOfl-propyl- 17u-ethynyl-A -estratriene-175-01, hydrolyzing thelatter under acid conditions to form 17a-ethynyl-10flpropyl-A-estradiene-17fi-ol-3-one and recovering the latter.

10. The process of claim 9 wherein the catalytic hydrogenation iseffected in the presence of palladized carbon black.

11. The process of claim 9 wherein the hydrolysis of the 3-loweralkylenedioxy-17fi-acyloxy-10fi-propyl-4,5- seco-A -estrene-S-One iseffected in the presence of acetic acid.

12. The process of claim 9 wherein the simultaneous cyclization andsaponification is effected with potassium hydroxide in methanol.

13. The process of claim 9 wherein the lower alkyl orthoformate is ethylorthoformate and the reaction is effected in the presence of p-toluenesulfonic acid.

14. The process of claim 9 wherein the alkali metal acetylide ispotassium acetylide.

15. The process of claim 9 wherein the hydrolysis of 3-lower alkoxy 17ccethynyl-10/3-pr0pyl-A -estratriene-17fi-ol is effected in the presenceof hydrochloric acid.

16. A process for the preparation of 17a-ethynyl-10fipropyl-A-estradiene-17fl-ol-3-one which comprises catalytically hydrogenating3-ethylenedioxy-17p-benzoyloxy-10 8-allyl-4,5-seco-A -estrene-5-0ne inthe presence of palladized carbon black to form3-ethylenedioxy-17flbenzoyloxy-1Ofi-propyl-4,5-seco-A -estrene-S-one,hydrolyzing the latter in the presence of acetic acid to form 173-benzoyl0xy 10,8 propyl-4,5-seco-A -estrene-3, S-dione, simultaneouslycyclizing and saponifying the latter in the presence of potassiumhydroxide in methanol to form 1OB-propyl-A -estradiene-17fl-ol-3-one,oxidizing the latter with chromium trioxide to form 1019- propyl-A-estradiene-3,17-dione, reacting the latter with ethyl orthoformate inthe presence of p-toluene sulfonic acid to form 3-ethoxy-10B-propyl-A-estratriene-17-one, reacting the latter with potassium acetylide Gouldet a1 Dec. 10, 1957 Agnello et a1. Apr. 21, 1959 Agnello et al. May 5,1959 OTHER REFERENCES Heyl et al.: J.A.C.S., 77 pp, 488-489 (1955),

1. A COMPOUND HAVING THE FORMULA
 9. A PROCESS FOR THE PREPARATION OF 17A-ETHYNYL-10BPROPYL-$4,9(11)-ESTRADIENE-17B-OL-3-ONE WHICH COMPRISESCATALYTICALLY HYDROGENATING 3-LOWERALKYLENEDIOXY-17BACYLOXY-10B-ALLYL-4,5-SECO-$9(11)-ESTRENE - 5 - ONEWHEREIN THE ACYL RADICAL IS DERIVED FROM AN ORGANIC CARBOXYLIC ACIDHAVING 1 TO 18 CARBON ATOMS IN THE PRESENCE OF A PALLADIUM CATALYST TOFORM 3-LOWERALKYLENEDIOXY-17BACYLOXY-10B-PROPYL-4,5-SECO-$9(11)-ESTRENE - 5 - ONE,HYDROLYZING THE LATTER UNDER ACIDIC CONDITIONS TO FORM 17BACYLOXY -10B - PROPYL-4,5-SECO-$9(11)-ESTRENE-3,5-DIONE, SIMULTANEOUSLY CYCLIZINGAND SAPONIFYING THE LATTER IN THE PRESENCE OF AN ALKALI-METAL HYDROXIDEIN A LOWER ALKANOL TO FORM 10B-PROPYL-$4,9(11)-ESTRADIENE-17B-OL-3-ONE,OXIDIZING THE LATTER WITH CHROMIUM TRIOXIDE TO FORM10B-PROPYL$4,9(11)-ESTRADIENE-3,17-DIONE, REACTING THE LATTER WITH ALOWER ALKYL ORTHOFORMATE TO FORM 3-LOWERALKOXY-10$-PROPYL-$3,5,9(11)-ESTRATRIENE-17-ONE, REACTING THE LATTERWITH AN ALKALI METAL ACETYLIDE TO FORM 3-LOWER ALKOXY-10B-PROPYL17A-ETHYNYL-$3,5,9(11)-ESTRATRIENE-17B-OL, HYDROLYZING THE LATTER UNDERACID CONDITIONS TO FORM 17A-ETHYNYL-10BPROPYL-$4,9(11)-ESTRADIENE-17B-OL-3-ONE AND RECOVERING THELATTER.